Project Summary The public health impact of patients suffering from neurodegenerative disorders such as Alzheimer disease (AD) is increasing at an alarming rate, both in the US and globally. Projections of the economic burden and lost productivity vary widely, but all estimates are disturbingly high. It is believed, for instance, that the number of patients diagnosed with AD will rise from the current value of 20-25 million worldwide to up to three times that number by 2050, assuming no effective treatment strategy emerges. Current approaches to try to curb the decline of cognitive function in AD, such as anti-amyloid immunotherapy, are showing only modest effect in the most recent clinical trials. Therefore, there is an immediate need to explore novel approaches to intervene or reverse the neuropathic effects associated with AD and related diseases. Among the most overt clinical symptoms of patients suffering from AD is the significant loss of memory and the inability to recall newly learned information. We hypothesize that a method that can improve memory and learning may, therefore, be an effective strategy to reverse the effects or slow down the progression of neurodegenerative diseases such as AD. In an effort to explore such a novel strategy, we have recently developed a synthetic molecule with drug-like properties (BTA-EG4) that exhibits the capability of improving memory and learning in wild type mice and in an AD mouse model and was also found to promote dendritic spine formation in neurons (in vivo and in vitro). Since dendritic spine density correlates strongly with memory and learning in human development, we hypothesize that the improved memory and learning in mice treated with BTA-EG4 is related to the capability of the molecule to promote spinogenesis. In order to follow up on these initial findings, this research seeks to gain a broader understanding of the activity of BTA-EG4 and related compounds. We will seek to better characterize the cellular machinery that is affected by BTA-EG4. Exciting preliminary data shows that we have tentatively identified the cellular target for BTA-EG4 through photoaffinity pulldown assays. This proposal seeks to 1) validate the cellular target of BTA-EG4 that leads to increase in dendritic spine density, 2) develop a family of BTA analogs to better characterize their capability to promote dendritic spines and to optimize spinogenic activity, and 3) explore whether BTA analogs can promote dendritic spine density in human neurons. The overall goal of this research will be the elucidation of the molecular mechanism of action of the BTA compounds that leads to an increase in dendritic spine density. A direct outcome of this research will be the identification of a new avenue for drug development leading to improved cognitive performance, which would represent an important and currently unavailable resource for the management of human mental health.